Tumor necrosis factors are a class of proteins produced by numerous cell-types, including monocytes and macrophages. At least two TNFs have been previously described, specifically TNF alpha and TNF beta (lymphotoxin).
These known TNFs have important physiological effects on a number of different target cells involved in the inflammatory response. The proteins cause both fibroblasts and synovial cells to secrete latent collagenase and prostaglandin E2, and cause osteoblastic cells to carry out bone resorption. These proteins increase the surface adhesive properties of endothelial cells for neutrophils. They also cause endothelial cells to secrete coagulant activity and reduce their ability to lyse clots. In addition they redirect the activity of adipocytes away from the storage of lipids by inhibiting expression of the enzyme lipoprotein lipase. TNFs cause hepatocytes to synthesize a class of proteins know as "acute phase reactants" and they act on the hypothalamus as pyrogens. Through these activities, it has been seen that TNFs play an important part in an organism's response to stress, to infection, and to injury. See, e.g., articles by P. J. Selby et al. in Lancet, Feb. 27, 1988, pg. 483; H. F. Starnes, Jr. et al. in J. Clin. Invest. 82:1321 (1988); A. Oliff et al. in Cell 50:555 (1987); and A. Waage et al. in Lancet, Feb. 14, 1987, pg. 355.
However, despite their normally beneficial effects, circumstances have come to light in which the actions of TNFs are harmful. For example, TNF alpha injected into animals gives rise to the symptoms of septic shock; endogenous TNF levels have been observed to increase following injection of bacteria or bacterial cell walls. TNFs also cause bowel necrosis and acute lung injury, and they stimulate the catabolism of muscle protein. In addition, the ability of TNFs to increase the level of collagenase in an arthritic joint and to direct the chemotaxis and migration of leukocytes and lymphocytes may also be responsible for the degradation of cartilage and the proliferation of the synovial tissue in this disease. Therefore, TNFs may serve as mediators of both the acute and chronic stages of immunopathology in rheumatoid arthritis. TNFs may also be responsible for some disorders of blood clotting through altering endothelial cell function. Moreover, excessive TNF production has been demonstrated in patients with AIDS and may be responsible for some of the fever, acute phase response and cachexia seen with this disease and with leukemias.
In these and other circumstances in which TNF has a harmful effect, there is clearly a clinical use for an inhibitor of TNF action. Systemically administered, TNF inhibitors would be useful therapeutics against septic shock and cachexia. Locally applied, such TNF inhibitors would serve to prevent tissue destruction in an inflamed joint and other sites of inflammation. Indeed, such TNF inhibitors could be even more effective when administered in conjunction with interleukin-I (IL-1) inhibitors.
One possibility for therapeutic intervention against the action of TNF is at the level of the target cell's response to the protein. TNF appears to act on cells through a classical receptor-mediated pathway. Thus, any molecule which interferes with the ability of TNF to bind to its receptors either by blocking the receptor or by blocking the TNF would regulate TNF action. For these reasons, proteins and small molecules capable of inhibiting TNF in this manner have been sought by the present inventors.